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1.
Immunogenetics ; 71(7): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31297569

RESUMO

Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


Assuntos
Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
2.
J Clin Exp Hematop ; 59(2): 56-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257346

RESUMO

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) with a T- or NK-cell phenotype are markedly rare, with only a limited number of cases having been reported thus far. Methotrexate (MTX) is the most common agent used for OIIA-LPD patients, and 43 cases of MTX-associated T-LPDs (MTX T-LPDs) and five cases of MTX-associated NK/T-LPDs (MTX NK-LPDs) have been described. In addition to MTX T-LPDs and MTX NK/T-LPDs, T-LPD and NK/T-LPDs have been reported in patients receiving other immunosuppressive agents such as thiopurines, TNF antagonists, and cyclosporine. Hepatosplenic T-cell lymphoma (HSTL) is specifically associated with iatrogenic immunodeficiency, and 10% of HSTL cases develop in patients receiving thiopurines and/or TNF antagonists for inflammatory bowel disease (IBD). In this review, we focused on MTX T-LPD, MTX NK/T-LPD, and HSTL in patients with IBD. These T- and NK/T-cell associated OIIA-LPDs are the most common in daily medical practice.


Assuntos
Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Animais , Humanos , Doença Iatrogênica/epidemiologia , Síndromes de Imunodeficiência/induzido quimicamente , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Transtornos Linfoproliferativos/induzido quimicamente , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , Linfócitos T/efeitos dos fármacos
3.
PLoS One ; 14(5): e0216815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071196

RESUMO

Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αß T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αß T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an "NK cell-promoting" protocol to differentiate γδ T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic γδ T cells endowed with an array of NKRs and thus designated as "γδ natural killer T (γδ NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, γδ NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.


Assuntos
Antígenos de Neoplasias/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos Quiméricos/imunologia , Antígenos de Neoplasias/genética , Células HCT116 , Células Hep G2 , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células K562 , Células MCF-7 , Células T Matadoras Naturais/patologia , Neoplasias/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos Quiméricos/genética , Células THP-1
4.
J Biol Chem ; 294(14): 5438-5455, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30745361

RESUMO

Asthma is a common inflammatory pulmonary disorder involving a diverse array of immune cells such as proinflammatory T helper 2 (Th2) cells. We recently reported that intraperitoneal injection of α-galactosylceramide (α-GalCer) can stimulate the lung invariant natural killer T (iNKT) cells and does not lead to airway inflammation in WT mice. Other studies indicate that iNKT cells play an important role in inducing regulatory T cells (Treg cells) and peripheral tolerance. Using iNKT cell- knockout mice, functional inactivation of Treg cells, and co-culture experiments in murine asthma models, we investigated the immunoregulatory effects of α-GalCer treatment before allergen sensitization on Th2 cell responses. We also studied whether α-GalCer's effects require lung Treg cells induced by activated iNKT cells. Our results disclosed that intraperitoneal administration of α-GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4+FoxP3+ Treg cells. These effects were accompanied by down-regulated Th2 cell responses and decreased immunogenic maturation of lung dendritic cells in WT mice. However, these changes were absent in CD1d-/- mice immunized and challenged with ovalbumin or house dust mites, indicating that the effects of α-GalCer on Treg cells mainly require iNKT cells. Moreover, functional inactivation of Treg cells could reverse the inhibitory ability of this α-GalCer therapy on Th2 cell responses in a murine asthma model. Our findings indicate that intraperitoneal administration of α-GalCer before the development of asthma symptoms induces the generation of lung Treg cells via iNKT cells and may provide a potential therapeutic strategy to prevent allergic asthma.


Assuntos
Alérgenos/toxicidade , Asma/prevenção & controle , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células T Matadoras Naturais/patologia , Pyroglyphidae/imunologia , Linfócitos T Reguladores/patologia , Células Th2/patologia
5.
J Exp Med ; 216(1): 133-151, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30518599

RESUMO

Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORγtneg) and MAIT17 (RORγt+) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1 and NKT17 subsets. The expression of similar programs was further supported by strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT subsets expressed gene signatures associated with tissue residency. Accordingly, parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver. The transcriptional program associated with tissue residency was already expressed in thymus, as confirmed by adoptive transfer experiments. Altogether, shared thymic differentiation processes generate "preset" NKT and MAIT subsets with defined effector functions, associated with specific positioning into tissues.


Assuntos
Células T Matadoras Naturais/imunologia , Timo/imunologia , Transcriptoma/imunologia , Animais , Feminino , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Fígado/imunologia , Fígado/patologia , Pulmão/imunologia , Pulmão/patologia , Antígeno-1 Associado à Função Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Células T Matadoras Naturais/patologia , Especificidade de Órgãos , Baço/imunologia , Baço/patologia , Timo/patologia
6.
Biochem Biophys Res Commun ; 508(2): 354-360, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30503343

RESUMO

PROBLEM: Recurrent spontaneous abortion (RSA) is associated with immune imbalance at the maternal-fetal interface. Decidual immune cells and cytokines expressed at this interface regulate the response of the maternal immune system to the fetus. However, the populations and cytokine expression levels of these lymphocytes in miscarriage with normal and abnormal chromosome karyotypes remain unclear. METHODS: We assessed the populations and cytokine expression levels of Natural Killer (NK), Natural Killer T (NKT), Helper T (Th) and Cytotoxic T (Tc) cells in the decidua of RSA by flow cytometry and simultaneously analyzed the fetal chromosome karyotypes of these miscarriages. RESULTS: Flow cytometry showed no significant difference between RSA and normal pregnancy in the percentages of Th, Tc, NK, and NKT cells. Type-1 cells decreased significantly in the decidua of normal pregnancy, and NK2 and NKT2 cells increased significantly in the normal pregnancy group. We also found no difference in the lymphocyte composition and the proportion of types 1 and 2 subsets of the four lymphocytes in the decidua between RSA with abnormal chromosome karyotypes of villous trophoblasts (RSA-A) and RSA with normal chromosome karyotypes of villous trophoblasts (RSA-N), but the proportion of type-1 cells in both groups was significantly higher than that in normal pregnancy. CONCLUSION: No difference existed between the type-1 immune response of RSA in normal and abnormal chromosome karyotypes of villous trophoblasts.


Assuntos
Aborto Habitual/genética , Aborto Habitual/imunologia , Aberrações Cromossômicas , Decídua/imunologia , Subpopulações de Linfócitos/imunologia , Aborto Habitual/patologia , Adulto , Estudos de Casos e Controles , Vilosidades Coriônicas/imunologia , Vilosidades Coriônicas/patologia , Citocinas/metabolismo , Decídua/patologia , Feminino , Humanos , Cariótipo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Subpopulações de Linfócitos/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Gravidez , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Trofoblastos/imunologia , Trofoblastos/patologia , Adulto Jovem
7.
Hum Cell ; 32(2): 141-149, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30539423

RESUMO

Natural killer T cells (NKT cells) and regulatory T cells (Treg cells) are two important immune regulatory cells which both play critical roles in asthma. Our previous experiments revealed that activation of Treg cells suppressed NKT cells in asthma. However, the possible regulatory effects and the mechanisms linking Treg cells and NKT cells remain poorly understood. The current study was designed to further investigate the regulatory effect and its possible mechanisms of Treg cells on NKT cells function, especially the distribution of NKT cells. Regulatory T cell (Treg), responder T cell (Teff) and Natural killer T cell (NKT) were isolated and purified. After Lentivirus carrying CD39 (Le-CD39) was transfected into Treg cells, the immune phenotype of Treg cells was changed and the suppressive effect of Treg cells on Teff cells with an activation of Treg cells was enhanced, marking with a high expression level of interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß). Up-regulation of CD39 expression led to lower ATP level in cell culture supernatant. To further explore its function in asthma, we introduced an ovalbumin (OVA)-induced mice model of asthma. And the data showed that up-regulation of CD39 remarkably alleviated OVA-induced hallmarks of the asthma and increased NKT cells in the spleen and peripheral blood; however, decreased NKT cells in the lung. Furthermore, up-regulation of CD39 decreased the levels of interleukin 4 (IL-4) and interferon γ (IFN-γ) in the lung of OVA-treated mice. Our results strongly suggest that Treg cells could be activated by CD39 signal transduction and then affected the distribution of NKT cells in the OVA-induced mice model of asthma.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Asma/imunologia , Células T Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apirase/genética , Apirase/metabolismo , Asma/patologia , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Células T Matadoras Naturais/patologia , Ovalbumina , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
8.
Mol Immunol ; 105: 213-223, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554082

RESUMO

Rapid onset of acute inflammation is a hallmark of critical illnesses that bring patients to the intensive care unit (ICU). In critical illness, innate T cells rapidly reach full activation and drive a robust acute inflammatory response. As "cellular adjuvants," innate T cells worsen inflammation and mortality in several common critical illnesses including sepsis, ischemia-reperfusion injury, stroke, and exacerbations of respiratory disease. Interestingly, innate T cell subsets can also promote a protective and anti-inflammatory response in sepsis, ischemia-reperfusion injury, and asthma. Therapies that target innate T cells have been validated in several models of critical illness. Here, we review the role of natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells in clinical and experimental critical illness.


Assuntos
Asma , Imunidade Inata , Unidades de Terapia Intensiva , Células T Matadoras Naturais , Traumatismo por Reperfusão , Sepse , Asma/imunologia , Asma/mortalidade , Asma/patologia , Asma/terapia , Humanos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Sepse/imunologia , Sepse/mortalidade , Sepse/patologia , Sepse/terapia
9.
Respir Res ; 19(1): 244, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30526599

RESUMO

BACKGROUND: Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function. METHODS: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. RESULTS: In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells - but not iNKT or NKT-like cells - were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results. CONCLUSIONS: In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02729220 .


Assuntos
Células Matadoras Naturais/metabolismo , Células T Matadoras Naturais/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/efeitos adversos , Fumar/metabolismo , Idoso , Estudos Transversais , Feminino , Seguimentos , Humanos , Células Matadoras Naturais/patologia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar/patologia , Abandono do Hábito de Fumar
10.
Front Immunol ; 9: 2168, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333822

RESUMO

T cells producing IFNγ play a pathogenic role in the development of inflammatory bowel disease (IBD). To investigate the functions of CD1d-dependent invariant natural killer T (iNKT) cells in experimental colitis induced in Yeti mice with dysregulated expression of IFNγ, we generated iNKT cell-deficient Yeti/CD1d KO mice and compared colitis among WT, CD1d KO, Yeti, and Yeti/CD1d KO mice following DSS treatment. We found that deficiency of iNKT cells exacerbated colitis and disease pathogenesis was mainly mediated by NK1.1+CD8+ T cells. Furthermore, the protective effects of iNKT cells correlated with up-regulation of regulatory T cells. Taken together, our results have demonstrated that CD1d-dependent iNKT cells and CD1d-independent NK1.1+CD8+ T cells reciprocally regulate the development of intestinal inflammatory responses mediated by IFNγ-dysregulation. These findings also identify NK1.1+CD8+ T cells as novel target cells for the development of therapeutics for human IBD.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Sulfato de Dextrana/toxicidade , Interferon gama/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Humanos , Interferon gama/genética , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Linfócitos T Reguladores/patologia
11.
Biochem Biophys Res Commun ; 506(1): 27-32, 2018 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-30336981

RESUMO

Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I-II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4+ or CD8+ T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E2. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.


Assuntos
Oxirredutases do Álcool/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Células Dendríticas/imunologia , Galactosilceramidas/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/terapia , Oxirredutases do Álcool/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/transplante , Dinoprostona/imunologia , Dinoprostona/metabolismo , Granzimas/genética , Granzimas/imunologia , Humanos , Imunoterapia/métodos , Interferon gama/genética , Interferon gama/imunologia , Células K562 , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Perforina/genética , Perforina/imunologia , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Transdução de Sinais , Análise de Sobrevida
12.
PLoS One ; 13(9): e0203228, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183741

RESUMO

Quinoline-3-carboxamides (Q substances) are small molecule compounds with anti-inflammatory properties. In this study, we used one of these substances, Paquinimod, to treat a novel model for chronic liver inflammation and liver fibrosis, the NOD-Inflammation Fibrosis (N-IF) mouse. We show that treatment of N-IF mice significantly reduced inflammation and resulted in the regression of fibrosis, even when the treatment was initiated after onset of disease. The reduced disease phenotype was associated with a systemic decrease in the number and reduced activation of disease-promoting transgenic natural killer T (NKT)-II cells and their type 2-cytokine expression profile. Paquinimod treatment also led to a reduction of CD115+ Ly6Chi monocytes and CD11b+ F4/80+ CD206+ macrophages.


Assuntos
Fatores Imunológicos/farmacologia , Cirrose Hepática/tratamento farmacológico , Quinolinas/farmacologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/patologia , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia
13.
Front Immunol ; 9: 1942, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210497

RESUMO

Innate T lymphocytes are a group of relatively recently identified T cells that are not involved in either innate or adaptive immunity. Unlike conventional T cells, most innate T lymphocytes express invariant T cell receptor to recognize exogenous non-peptide antigens presented by a family of non-polymorphic MHC class I-related molecules, such as CD1d and MHC-related molecule-1 (MR1). Invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells quickly respond to the antigens bound to CD1d and MR1 molecules, respectively, and immediately exert effector functions by secreting various cytokines and granules. This review describes the detrimental and beneficial roles of iNKT cells in animal models of asthma and in human asthmatic patients and also addresses the mechanisms through which iNKT cells are activated by environmental or extracellular factors. We also discuss the potential for therapeutic interventions of asthma by specific antibodies against NKT cells. Furthermore, we summarize the recent reports on the role of MAIT cells in allergic diseases.


Assuntos
Antígenos CD1d/imunologia , Asma/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Animais , Asma/patologia , Humanos , Células T Invariáveis Associadas à Mucosa/patologia , Células T Matadoras Naturais/patologia , Receptores de Antígenos de Linfócitos T/imunologia
14.
Int J Mol Sci ; 19(8)2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30103488

RESUMO

Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Melanoma/terapia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T , Humanos , Células Jurkat , Melanoma/genética , Melanoma/imunologia , Células T Matadoras Naturais/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia
15.
Biol Blood Marrow Transplant ; 24(12): 2471-2478, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30064012

RESUMO

Natural killer (NK)/T cell lymphoid malignancy comprises extranodal NK/T cell lymphoma (ENKTL) and aggressive NK cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease. We retrospectively analyzed 36 patients (ENKTL, n = 26; ANKL, n = 10) who underwent upfront (n = 19) and salvage allogeneic SCT (n = 17) at 6 hospitals. Patients received myeloablative (n = 25) or reduced-intensity (n =11) conditioning regimens depending on the institute's policy. The median age at the time of allogeneic SCT was 37 years (range, 17 to 62), and more patients with ANKL (8/10) received upfront allogeneic SCT than ENKTL patients (11/26). Disease status before allogeneic SCT, conditioning regimen, and donor source did not differ between upfront and salvage allogeneic SCT groups. Febrile neutropenia (n = 20) and acute graft-versus-host disease (n = 16) were common adverse events. The median overall survival (OS) and progression-free survival (PFS) after allogeneic SCT were 11.8 months and 10.0 months, respectively. Twelve patients died from disease relapse and 12 from nondisease-related causes. Ten deaths occurred within 100 days after allogeneic SCT (10/24); these were mostly related to disease relapse (n = 8). The OS after allogeneic SCT did not differ between ENKTL and ANKL (P = .550) or between upfront and salvage SCT (P = .862). Complete chimerism was significantly associated with better PFS (P < .001). No significant differences in PFS were observed based on the conditioning regimen or source of stem cells (P > .05). Allogeneic SCT may be beneficial for patients with ENKTL and ANKL given that some patients were able to maintain their remission after allogeneic SCT. However, allogeneic SCT should only be performed in highly selected patients because the risks of disease relapse and nondisease-related mortality remain high.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Linfoide/terapia , Células T Matadoras Naturais/metabolismo , Terapia de Salvação/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Feminino , Humanos , Leucemia Linfoide/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Adulto Jovem
16.
Histopathology ; 73(6): 1030-1038, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30102799

RESUMO

AIMS: Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. METHODS AND RESULTS: We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10). CONCLUSIONS: Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.


Assuntos
Linfoma Extranodal de Células T-NK/metabolismo , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Adulto Jovem
17.
Nat Commun ; 9(1): 2812, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-30022064

RESUMO

The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-γ-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Autofagia/genética , Interleucina-15/genética , Mitocôndrias/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Autofagia/imunologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/imunologia , Sobrevivência Celular , Regulação da Expressão Gênica , Interferon gama/genética , Interferon gama/imunologia , Interleucina-15/imunologia , Ativação Linfocitária , Contagem de Linfócitos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/patologia , Células T Matadoras Naturais/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
18.
Curr Hematol Malig Rep ; 13(4): 308-317, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29943210

RESUMO

PURPOSE OF REVIEW: To provide an update on the pathogenesis of enteropathy-associated T cell lymphoma (EATL) and its relationship with refractory celiac disease (RCD), in light of current knowledge of immune, genetic, and environmental factors that promote neoplastic transformation of intraepithelial lymphocytes (IELs). RECENT FINDINGS: EATL frequently evolves from RCD type II (RCD II) but can occur "de novo" in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL. The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.


Assuntos
Doença Celíaca , Linfoma de Células T Associado a Enteropatia , Mucosa Intestinal , Intestino Delgado , Células T Matadoras Naturais , Doença Celíaca/complicações , Doença Celíaca/genética , Doença Celíaca/imunologia , Doença Celíaca/patologia , Linfoma de Células T Associado a Enteropatia/genética , Linfoma de Células T Associado a Enteropatia/imunologia , Linfoma de Células T Associado a Enteropatia/patologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/imunologia , Intestino Delgado/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia
19.
Cardiovasc Pathol ; 35: 1-7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29727769

RESUMO

INTRODUCTION: Aortic stenosis (AS) is the most common acquired valvular heart disease in adults. Immune system involvement becomes evident during AS development. We sought to investigate the role of different circulating lymphocyte and monocyte subpopulations, with focus on CD4+CD8+ and natural killer T (NKT) cells, in AS. MATERIAL AND METHODS: Blood samples and aortic valves were obtained from patients undergoing elective aortic valve surgery. Valves were dissected and underwent genetic analyses and calcium content assessment. Lymphocytes and monocytes subsets were assessed by flow cytometry. RESULTS: Thirty-eight AS patients were studied. Maximal transvalvular pressure gradient (PGmax) as well as mean transvalvular pressure gradient (PGmean) correlated with the CD4+CD8+ lymphocyte count (r=0.35, P=.03 and r=0.43, P=.006, respectively) and fraction (r=0.43, P=.007 and r=0.48, P=.002, respectively). PGmax and PGmean correlated with CD16+CD56+CD3+ NKT cell count (r=0.39, P=.01 and r=0.43, P=.007, respectively) and fraction (r=0.49, P=.002 and r=0.47, P=.003, respectively). The classical monocyte subpopulation increased after the surgery by 68% (P<.0001). Patients after mini-sternotomy surgery had 47% lower nonclassical monocyte counts than those with full-sternotomy (P=.03). Patients treated with statins had significantly lower postoperative levels of both classical (-25%, P=.04) and nonclassical monocytes (-37%, P=.004) than nontreated individuals. CONCLUSIONS: In patients with severe isolated AS, CD4+CD8+ T cells and CD16+CD56+CD3+ NKT cells are associated with AV pressure gradients. Postoperative monocyte levels are affected by procedure invasiveness and use of statins.


Assuntos
Estenose da Valva Aórtica/imunologia , Valva Aórtica/imunologia , Valva Aórtica/patologia , Calcinose/imunologia , Monócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Valva Aórtica/fisiopatologia , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/cirurgia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Calcinose/patologia , Calcinose/fisiopatologia , Calcinose/cirurgia , Procedimentos Cirúrgicos Cardíacos , Feminino , Citometria de Fluxo , Hemodinâmica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Monócitos/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Fenótipo , Índice de Gravidade de Doença , Esternotomia , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/patologia , Resultado do Tratamento
20.
Pathol Res Pract ; 214(7): 1051-1055, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29843925

RESUMO

Extranodal NK/T cell lymphoma, nasal type (ENKL) developed in a patient with intestinal Epstein-Barr virus (EBV)-positive T/NK-cell lymphoproliferative disorder (LPD). The patient was a 46-year-old Chinese man who complained of diarrhea and abdominal pain without immune-deficiency. Endoscopy demonstrated ileum ulcers like Crohn's disease, without histological granulomas. His symptoms continued waxing and waning for 3 years until he developed overt lymphoma (ENKL) in the nasal cavity. The ileum lesions exacerbated into a large deep ulcer, and the biopsy specimens from the ileum, including the one 3 years ago, showed infiltration of small lymphocytes containing many EBV-positive T/NK cells without atypia. Thus, the patient illness of intestine was revealed as intestinal EBV-positive T/NK-cell LPD, which might be closely associated with development of ENKL in this patient. In cases of inflammatory bowel disease without typical clinical courses and histological findings, check-up of EBV in the biopsy might help correct diagnosis.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Linfoma Extranodal de Células T-NK/virologia , Transtornos Linfoproliferativos/patologia , Cavidade Nasal/patologia , Células T Matadoras Naturais/virologia , Biópsia , Infecções por Vírus Epstein-Barr/patologia , Humanos , Intestinos/patologia , Intestinos/virologia , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/patologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/diagnóstico por imagem , Células T Matadoras Naturais/patologia
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